{107 -guanidino acid diamide derivatives and manufacturing the same

ABSTRACT

The present omega -guanidino acid diamide derivatives are new compounds having a structural formula of   WHEREIN M IS AN INTEGER OF 1 TO 10 AND R is an alkylene of one to 12 carbon atoms or   D R A W I N G

United States Patent [191 'Hashimoto et al.

[ Mar. 26, 1974 [73] Assignee: Taiho Pharmaceutical Company Limited,Tokyo, Japan [22] Filed: Apr. 2, 1970 [21] Appl. No.: 25,240

[30] Foreign Application Priority Data Apr. 2, 1969 Japan 44-25806 [52]US. Cl..... 260/561 A, 260/501.l4, 260/562 N,

260/999 [51] Int. Cl. C07c 103/50 [58] Field of Search 260/50l.l4, 561A, 562 N [56] References Cited OTHER PUBLICATIONS Hafner et al. J. Am.Chem. Soc. Vol. 79, pgs. 3,783-3,786 (1957) Fujii, Chemical Abstracts,Vol. 71, 49602c (1969) Horlicks Ltd., Chemical Abstracts, Vol. 71,80752a Primary ExaminerLeon Zitver Assistant ExaminerMichael W. GlynnAttorney, Agent, or FirmLarson, Taylor and Hinds [5 7] ABSTRACT Thepresent w-guanidino acid diamide derivatives are new compounds having astructural formula of wherein m is an integer of 1 to 10 and R is analkylene of one to 12 carbon atoms or 0 Hi) n,

n being 0 or an integer of l to 3. The above derivatives and onium saltsthereof are excellent in pharmacological activity, particularly inantagonism to bradykinin and inhibition of edema, and thus useful asantiinflammatory agent.

8 Claims, No Drawings w-GUANIDINO ACID DIAMIDE DERIVATIVES ANDMANUFACTURING THE SAME This invention relates to new and usefulw-guanidino acid diamide derivatives and onium salts thereof having highorder of pharmacological activity and to a process for manufacturingthem.

The w-guanidino acid diamide dirivatives of the invention are of thefollowing formula:

NHz NH:

CNH(CHz)mCONHRNHOC(CHz)mNHC (I) .ISH NH Wherein m is an integer of l toand R is an alkylene of one to 12 carbon atoms or (CH2)u,

n'being 0 or an integer of l to 3.

The present diamide derivatives having the above formula (I) and oniumsalts thereof are excellent in pharmacological activity, particularly inantagonism to bradykinin and inhibition of edema, and thus useful asanti-inflamatory agent.

The representative examples of the amide derivatives of the inventionare listed in the Table 1 below, in which the melting points show thoseof the acetic acid Of these compounds particularly preferable arebis(e-guanidinocaproyl) hexamethylene diamide(I-2),bis(e-guanidinocaproyl) dodecamethylene diamide(l-3), etc.

The diamide derivative of the invention may be prepared by variousmethods, but it is preferable to produce it by reducing anwnitroguanidino acid diamide derivative having the formula (II) belowwith hydrogen gas, the reaction being shown in the followin g et atitNOzNH NHN02 +H CNH(CH1)mCONHRNHOC(CHz)mHNC -3 y NH NH NE /NH;

CNH(CH))mCONHRNHO C (CH2)mHNC NE NH wherein R and m are the same asdefined before. This reaction may be conducted in various manners, forexample, by introducing hydrogen gas into a solvent solution of thecompound (II). Preferable solvents for the purpose are formic acid,acetic acid, propionic acid. a mixture of methanol and hydrochloricacid. etc. and by the use of such as a acid solvent the present diamidederivatives can be obtained in the form of onium salts which are moreexcellent in stability and watersolubility than the diamides themselves.The temperature of the reduction may be in the range of a roomtemperature to a boiling point of the solvents used. but preferably itis performed at a moderately elevated temperature of about 60 to C. Toaccelerate the reaction conventional reducing catalysts such aspalladium black, palladium charcoal, etc. may be used.

The compound (II) used as a starting material in the above reaction isan oily or crystalline novel substance insoluble in water and examplesthereof are listed in the following Table 2 below:

The compound (II) above can preferably be prepared by the followingmethods (A) to (C), using e-nitro-guanidino acid (III) as a startingmaterial, though it may also be produced by other methods.

METHOD (A) The reactions involved in this method are represented asfollows:

wherein R and m are the same as defined before, and R is a lower alkylof one to four carbon atoms.

The starting w-nitroguanidino acids (Ill) are known in the art and maybe easily prepared by nitrating w-guanidino acid with fuming nitric acidat a temperature of l0 to +10 C. The fuming nitric acid may preferablybe used in admixture with one or both of fuming sulfuric acid andconcentrated nitric acid. Ammonium nitrate dissolved in sulfuric acidmay also be used as a nitrating agent. Alternatively thew-nitioguanidino acid can be prepared by the reaction of w-amino acidwith 2-methyl-l-nitro isourea in an alkali solution. This I method isknown in the art and described in detail in the appended Example 5. Bythe introduction of a nitro group to w-guanidio acid the guanidino groupin the resultant w-nitroguanidino acid is rendered stable in thesubsequent chemical reactions, thus enabling the production of thedesired w-nitroguanidino acid diamide derivatives (II) in a high orderof yield with the minimum production of byproducts.

The reaction of w-nitroguanidino acid (III) with a loweralkylchlorocarbonate to produce mixed anhydride (IV) may be carried outin the presence of a solvent, such as N.N-dimethyl formamide, toluene,chloroform, etc. at a temperature of-lO to +10 C, preferably -5 to C.Preferable alkylchlorocarbonates are ethylchlorocarbonate,isobutylchlorocarbonate. To accelerate the reaction adehydrochlorinating agent, such as triethyl amine, tri-n-butyl amine andlike tertiary bases may be added to the reaction system. The resultantmixed anhydride (IV) is then subjected to the subsequent reaction with aprimary diamine to produce an w-nitroguanidino acid diamide (II).Various diamines may be used, but primary amines having to 12 carbonatoms are preferable. The reaction may be carried out at a temperatureof to +10 C, preferably 5 to 0C. The resultant w-nitroguanidino acidamide (II) may easily be separated from the reaction mixture by addingwater thereto.

METHOD (B) In this hei hqf llqwinar s iw -er uwh l;

NOzNH CNH(CH:) CO0H (III) wherein R and m are the same as definedbefore.

According to this method w-nitroguanidino acid (III) is reacted withp-nitrophenol to produce p-nitrophenyl ester of w-nitroguanidino acid(V). This reaction may preferably be carried out in an inert solventsuch as N,N-dimethyl formamide in the presence of dehydrating agent,such as hexylcarbodiimide. The reaction temperature may usually be aroom temperature. In the place of p-nitrophenol may be useddi-p-nitrophenyl sulfite, tri-p-nitrophenyl phosphite, etc, and in thiscase the reaction is conducted in a solvent such as pyridine or amixture of pyridine and ethylacetate at a room temperature or moderatelyelevated temperature of 50 to 60 C.

The resultant ester (V) is then reacted with a primary diamine toproduce the desired compound (II). This reaction may be carried out inthe presence of solvents, such as chloroform, methyl acetate,N,N-dimethyl formamide, etc. The reaction temperature may usually be aroom temperature.

METHOD (C) wherein R and m are the same as defined before, and R" is alower alkyl of one to four carbon atoms.

The esterification reaction to produce ester (VI) may be carried out byconventional methods. For example, w-nitroguamidino acid (III) isreacted with a lower alcohol cooled with ice water while introducing dryhydrochloric acid gas. The reaction may also be conducted by refluxing alower alcohol in the presence of p-toluene sulfonic acid, benzenesulfonic acid, etc. To the resultant ester (VI) is added excess amountof hy- NHNO:

drazine and the mixture is left standing at a room temperature ormoderately elevated temperature of 50 to C to produce w-nitroguanidinoacid hydrazide (VII). The hydrazide (Vll) is dissolved in hydrochloricacid, acetic acid or like acid and cooled to lower than 0 C, to whichsodium nitrite is added, whereby azide (VIII) can be obtained. Theresultant azide is reacted with a diamine at l0 to +5 C to producew-nitroguamidino acid amide derivative (II).

For better understanding of the invention examples of preparing thepresent diamne derivatives and pharmacological activities thereof areshown below.

EXAMPLE 1 m1 of fuming nitric acid was added with stirring to a solutionof 60 ml of fuming sulfuric acid and 40 ml of concentrated sulfuric acidcooled with ice. While the temperature of the resultant liquid wasmaintained at lower than 10 C, 65.7 g of e-guanidinocaproic acid wasadded stepwise thereto. After completion of the addition the solutionwas further stirred continuously for 2 hrs in the ice bath. Theresultant reaction solution was poured into 1 kg of ice with stirring,and the precipitated crystals were filtered and washed with water. By

recrystallization from hot water 64.8 g of white needlelike crystals ofs-nitroguanidinocaproic acid, melting at 156.5 to 158 C. was obtained.The yield was 78.2 Elementary analysis thereof gave the followingresults:

C H N Calcd(C H O N.): 38.53% 6.47% 25.68% Found: 38.72% 6.24% 26.00%

9.6 g of e-nitroguanidinocaproic acid thus obtained and 4.5 g oftriethylamine were dissolved in 50 ml of N ,N-dimethylformamide. To thesolution was added dropwise with stirring 4.8 g of ethyl-chlorocarbonateat to C. After the addition the mixture was further stirred for min. Tothe resultant mixture was added dropwise with stirring at 0 to 5 C, 4.0g of 1,12- dodecamethylene diamine dissolved in 100 ml of chloroform,after which stirring was continued for one hour at the temperature andthe mixture was left standing at room temperature overnight toprecipitate the crystals. The precipitated crystals were filtered andwashed with water. Recrystallization from N,N-dimethylformamide gave 9.6g of white crystals of 1,12-bis-(enitroguanidinocaproyl) dodcamethylenediamide. The yield was 79.9 This product has a melting point of 167 to169 C and elementary analysis thereof gave the following results:

C H N Ca1cd(C,,l-l, N,,,O.,): 51.98% 8.72% 23.31% Found: 51.58% 9.00%23.14%

3 g of l,12-bis-(e-nitroguanidinocaproyl) dodecamethylene diamide thusobtained was dissolved in 50 ml of glacial acetic acid and palladiumblack was added to the solution. Then hydrogen gas was introduced to themixture at 70 to 80 C for 8 hrs. and further passed therethrough at roomtemperature for 9 hrs. Palladium black was then removed by filtrationand the mixture was concentrated under reduced pressure.Recrystallatization from ethanol-ether gave 2.9 g of white powderycrystals of l,l2-bis-(e-guanidinocaproyl) dodecamethylene diamidediacetate having a melting point of 123 to 125 C. The yield 91.9

Sakaguchi reaction of the product was positive and elementary analysisthereof gave the following results:

C H N Ca1cd(C H, O,N.,.

ZCH COOH): 57.12% 9.91% 17.76% Found: 56.79% 10.11% 18.01%

The pharmacological activity of the compound was tested and thefollowing results were obtained: 1. Antagonistic action on bradykinin Hr a. Depressive action on contraction of smooth muscle Through the testfor the depressive effect of the compound on the contration of isolateduterus muscle of rats by bradykinin, the compound exhibited a markeddepressive action at a concentration of 10" mol/lit.

The depressive action of the compound is by far stronger than varioussubstances which have been recognized as having antLbradykinin action.

b. Depressive action on vascular permeability The depressive action ofthe compound on the acceleration of vascular permeability in the case ofsubcutaneous administration of bradykinin to rabbits, rats, mice, etc.was tested and a marked depressive action was exhibited by the dose of10 mg/kg.

2. Depressive action on edema The depressive action of the compound onthe increase of edema with the passage of time when carra geenin wasadministered through the heel of rats was tested, and by administrationof a dose of 10 mg/kg, the edema was markedly depressed.

EXAMPLE 2 24.0 g of e-nitroguanidinocaproic acid and 1 1.1 g oftriethylamine were dissolved in ml of N,N-dimethylformamide. To thesolution cooled to 0 to 5 "C was added dropwise 11.9 g ofethylchloro-carbonate with stirring, after which the mixture was furtherstirred for 15 min. To the resultant reaction mixture was dropwise addedslowly at 0 to 5 "C 5.8 g of 1.6- hexamethylenediamine dissolved in amixed solvent of 60 ml of N,N-dimethylformamide and 60 ml of chloroform,and further stirred at the temperature for one hour, and left standingat room temperature over-night. The reaction mixture was poured intowater with stirring and the precipitated crystals were filtered.Recrystallization from N,N-dimethylformamide gave 16.8 g of whitecrystals of 1,6-bis(e-nitroguanidinocaproyl) hexamethylene diamidehaving a melting point of 174 C. The yield was 65.1 and elementaryanalysis thereof gave the following results:

. N Calcd(C ,,H N, O 46.50% 7.80% 27.11% Found: 46.74% 8.01% 27.42%

of 1.6 bis(e-nitroguanidinocaproyl) hexamethresults:

c H N ca|d c,,,i-i.,N.,o,.

2CH COOH 52.73% 9.22% 20.50% Found: 52.41% 9.48% 20.73%

The depressive action of the compound on the contraction of isolateduterus muscle of rats by bradykinin was tested, and the compoundexhibited a marked depressive action at a concentration of 10 mol/lit.

EXAMPLE 3 14.2 g of e-nitroguanidinocapric acid and 5.6 g oftriethylamine were dissolved in 60 ml of N,N-dimethylformamide. To thesolution cooled to O to 5C 6 g of ethylchlorocarbonate was addeddropwise with stirring, after which the stirring was continued for 15min. To the mixture was dropwise added slowly 1.8 g of ethylene diaminedissolved in 30 ml of N,N-dimethylformamide, and after further stirringat the temperature for 1 hour the solution was left standing overnight.The resultant reaction mixture was poured into water with stirring, andthe precipitated crystals were filtered. Recrystallization gave 10 g ofwhite powdery crystals of bis(enitroguanidinocaproyl) ethylenediamidehaving a melting point of 230 231C. The yield was 76.2 The elfromN,N-dimethylformamide-ether ementary analysis thereof gave the followingresults:

c H N Calcd(C,.,H;, N,.,O,.): 41.73% 7.00% 30.43% Found: 42.00% 7.27%30.68%

Sakaguchi reaction of the compound was positive and elementary analsisthereof gave the following results:

c H N c.11cd c,,,H..N,.o,.

ZCHHCOOH): 48.96% 8.63% 22.84% Found: 48.85% 8.75% 23.08%

The depressive effect of the compound on the contraction of isolateduterus muscle of rats by bradykinin was tested, and marked depressiveaction was exhibited at a concentration of l mol/lit.

EXAMPLE 4 14.4 g of e-nitroguanidinocaproic acid and 6.7 g oftriethylamine were dissolved in 50 ml of-N,N-dimethylformamide. To thesolution cooled to O to 5C 7.2 g of ethyl chlorocarbonate was dropwiseadded with stirring, after which further stirred for min. To the mixturewas dropwise added slowly 4.1 g of mxylylenediamine dissolved in 25 mlof N,N-dimethylformamide, and after being stirred at the temperature for1 hour the mixture was left standing overnight. The reaction mixture waspoured into water with stirring and the precipitated crystals werefiltered and recrystallized from dimethylformamide, whereby 10.5 g ofl,3-bis(enitroguanidinocaproyl)xylylenediamide, melting at 157 162C wasobtained. The yield rate of 66 The elementary analysis gave thefollowing results:

C H N Calcd(C H N,,,O,,): 49.24% 6.76% 26.10% Found: 49.55% 6.95% 26.29%

5.4 g of l,3-bis(e-nitroguanidinocaproyl)xylylene diamide was dissolvedin 70 ml of glacial acetic acid, and palladium black was added thereto.The mixture was then reduced at 70 80C for 15 hrs. by introducinghydrogen gas, then palladium black was removed by filtration, andconcentrated under reduced pressure. The resultant oily substance wasthoroughly washed with ethanol-ether, whereby slightly yellowishtransparent tacky and oily substance, l,3-bis(eguanidinocaproyl)xylylenediamide was obtained.

This compound showed positive in Sakaguchi reaction and exhibited amarked depressive action at a concentration of l0 mol/lit on thecontraction of isolated uterus muscle of rats by bradykinin.

EXAMPLE 5 5.4 g of e-aminocaproic acid was dissolved in a mixture of 40ml of water and ml of ZN-sodium hydroxide, and under cooling 4.8 g ofZ-methyl-l-nitroisourea was slowly added thereto. After 2 hour stirring,the

mixture was acidified with hydrochloric acid to precipitate crystals.The precipitated crystals were filtered and recrystallized from hotwater. whereby 3.8 g of white needle-like e-nitro-guanidinocaproic acid,melting at 15 6- l 5 8C, was 5bT5ined:

C H N Calcd(C H O N;): 38.53% 6.47% 25.68% Found: 38.23% 6.42% 25.78%

e-nitroguanidinocaproic acid was also prepared by the following method:

In 20 ml of concentrated sulfuric acid cooled to less than 10C wasdissolved 8.7g of e-guanidinocaproic acid. To the solution was added 5.2g of ammonium nitrate with stirring and the stirring was continued for 2hrs. The mixture was thereafter poured into ice water to precipitatecrystals. The precipitated crystals were recrystallized from hot water,whereby 6.5 g of white needle-like e-nitroguanidinocaproic acid, meltingat 156 1 58C, v\ as oliainedf c H N ca16d(c,H,,o.N,1. 38.53% 6.47%25.68% Found: 38.59% 6.52% 25.84%

4.3 g of e-nitroguanidinocaproic acid thus obtained and 3.1 g ofp-nitrophenol were dissolved in 30 ml of N,N-dimethylformamide, andunder cooling 4.4 g of dicyclohexylcarbodiimide was added thereto, andafter stirring for 3 hrs. the precipitated substance was removed byfiltration. To the filtrate water was added to precipitate the crystals.By recrystallization from N,N-dimethylformamide-water 2.9 g of yellowpowdery p-nitrophenyl ester of e-nitro-guanidinocaproic acid having amelting point of 111 112.5C was obtained. Elementary analysis thereofgave the following 7 results:

2.. ..i 22 ca1cd c..H,,o,N, 46.03% 5.05% 20.65% Found: 45.72% 5.17%20.48%

8 g of p-nitrophenyl ester of e-nitroguanidinocaproic acid and 3 g of1,lZ-dodecamethylenediamine were dissolved in 40 ml ofN,N-dimethylformamide, and left standing overnight at room temperature.After the rementary analysisthereof gave the following results:

C H N ca1d c,..H,,N o, 51.98% 8.72% 23.31% Found: 52.01% 8.46% 23.37%

In the similar method as in Example 1l,l2-bis(enitroguanidinocaproyl)dodecamethylenediamide was reduced,whereby 3.4 g of white powderyl,l2-bis(eguanidinocaproyl)dodecamethylenediamide diacetate, melting at123 125C, was obtained. Elementary analysis thereof gave the followingresults:

C H N Calcd(C, l-l O N,.

zcn coom; 57.12% 9.91% 17.76% Found: 56.83%

At the concentration of lO' mol/lit, the resultant compound exhibiteddepressive action on the contrac- 9 tion of isolated u terus miiscleratsby bradyldnin. Also notable depressive action was exhibited on theacceleration of vascular permeability in intracutaneous administrationof histamine to guinea-pig with a dose of 10 mg/kg (intra peritonealadministration).

EXAMPLE 6 C H N Calcd(C H ,N, O,,): 41.73% 7.00% 30.43% Found: 41.57%7.18% 30.72%

4.6 g of bis(e-nitroguanidinocaproyl)ethylenediamide was suspended in200 ml of glacial acetic acid, to which was added palladium black.Hydrogen gas was introduced to the mixture at 70 80C for 20 hrs, andpalladium black was then removed by filtration. The filtrate wasconcentrated under reduced pressure, and by recrystallization frommethanol-ether, 3.2 g of white powderybis(e-guanidinoc'aproyl)ethylenediamide diacetate, melting at 215 218C,was obtained. Elementary analysis thereof gave the following results:

C H N Calcd(C H N,,O,.

2CH;COOH): 48.96% 8.63% 22.84% Found: 48.65% 8.87% 23.08%

By the test of the compound in the manner similar to that of Example 1,depressive action was observed on bradykinin at the concentration of 10'mol/lit.

EXAMPLE 7 21.8 g of e-nitroguanidinocaproic acid was suspended in 450 mlof methanol, and the suspension was stirred under cooling, whileintroducing hydrogen chloride gas until the acid was thoroughlydissolved. After the reaction the mixture was concentrated under reducedpressure, and water was added to the residue to precipitate thecrystals. By recrystallization from methanol-ether l l g of whiteneedle-like e-nitroguanidinocaproic acid methyl ester, melting at 99100C was obtained. Elementary analysis thereof gave the followingresults:

c 1-1 N Calcd(C,l-l ,N O,): 41.37% 6.94% 24.12% Found: 41.33% 7.19%24.30% v 8. 1 g of e-nitroguanidinocaproic acid methyl ester wasdissolved in ml of methanol. To the solution was added 4.3 g ofhydrazine hydrate and left standing at room temperature for 40 hrs.Ether was thereafter added to the reaction mixture to precipitatecrystals. By recrystallization from ethanol-ether 4.1 g of whitee-nitroguanidinocaproylhydrazide, melting at 141 to 145C was obtained.Elementary analysis thereof gave the following results:

5.5 g of e-nitroguanidinocaproylhydrazide was dissolved in 60 ml oflN-hydrochloric acid, and under cooling 29 ml of 1N sodium nitrite wasadded thereto. The separated product was extracted with ethyl acetate,and to the ethyl acetate layer was added under cooling 1.2 g of1,6-hexamethylenediamine dissolved in 10 ml of ether. After beingstirred for two hrs the mixture was left standing overnight. Then etherwas added thereto to precipitate crystals and the precipitated crystalswere filtered and recrystallized from N,N-dimethylformamide-ether,whereby 3.1 g of whitel,6-bis(enitroguanidinocaproyl)hexamethylenediamide, melting at 174C,was obtained. Elementary analysis thereof gave the following results:

C H N Calcd(C ,,H .,N O,,): 46.50% 7.80% 27.11% Found: 46.72% 7.69%27.46%

C H N Calcd(C H N,,O,.

2CH;COOH): 52.73% 9.22% 20.50% Found: 52.38% 9.37% 20.82%

The resultant compound was tested in the manner similar to that ofExample 3 and exhibited depressive action on bradykinin, at theconcentration of 1O mol/- lit.

3 C EXAMPLE 8 5.5 g of e-nitroguanidinocaproylhydrazide obtained in thesame manner as in Exampel 7 was dissolved in 60 ml of lN-hydrochloricacid, and the undercooling 29 ml of 1N sodium nitrite was added thereto.The separated product was extracted with ethyl acetate, and to the ethylacetate layer was added 1.4 g of mxylylenediamine dissolved in 10 ml ofether under cooling. After being stirred for two hours the mixture wasleft standing overnight. Then ether was added thereto to precipitatecrystals. The precipitated crystals were filtered and recrystallizedfrom N,N-dimethylformamide-water, whereby 27.8 g of1,3-bis(enitroguanidecaproyl)xylylenediamide, melting at 157 to 162C,was obtained. Elementary analysis thereof gave the following results:

C H N Calcd(C, H,.,N ,0,,): 49.24% 6.76% 26.10% Found: 49.09% 6.97%26.32%

In the same manner as in Example 4,l,3-bis(enitroguanidinocaproyl)xylylenediamide was reduced with hydrogengas whereby 1.4 g of l,3-bis(eguanidinocaproyl)xylylenediamide diacetatewas obtained as a light yellow transparent tacky and oily substance.

The depressive action of the compound on bradykinin was exhibited at theconcentration of 10 mol/lit in the test similar to that of Example 3.

What we claim is:

1. An m-guanidino acid diamide derivative having the formula herein m isan integer of 1 to 10 and R is an alkyl ene of one to 12 carbon atoms orn being or an integer of l to 3.

2. The w-guanidino acid diamide derivative according to claim 1, inwhich said R is an alkylene of one to 12 carbon atoms.

3. The w-guanidino acid diamide derivative according to claim 1, inwhich said R is 8. The w-guanidino acid diamide derivative according toclaim 1, in which said m is an integer of 5 and R is xylylene.

2. The omega -guanidino acid diamide derivative according to claim 1, inwhich said R is an alkylene of one to 12 carbon atoms.
 3. The omega-guanidino acid diamide derivative according to claim 1, in which said Ris
 4. The omega -guanidino acid diamide derivative according to claim 1,in which said m is an integer of
 5. 5. The omega -guanidino acid diamidederivative according to claim 1, in which said m is an integer of 5 andR is ethylene.
 6. The omega -guanidino acid diamide derivative accordingto claim 1, in which said m is an integer of 5 and R is hexamethylene.7. The omega -guanidino acid diamide derivative according to claim 1, inwhich said m is an integer of 5 and R is dodecamethylene.
 8. The omega-guanidino acid diamide derivative according to claim 1, in which said mis an integer of 5 and R is xylylene.